Adult mammalian Hg is a multimeric protein that includes two α and two β globin chains which together form the (α/β)2 tetrameric hemoglobin (Hb) molecule. Beta-thalassemias are a group of inherited blood disorders caused by a quantitative defect in the synthesis of the β chains of hemoglobin. In individuals with this disorder, the synthesis of β-globin chains is reduced or absent. Three main forms of the disease have been described: β-thalassemia major β-TM or β0-TM) in which no β chain is produced, and β-thalassemia intermedia and β-thalassemia minor, in which β chain is produced but in lower than normal amounts. These conditions cause variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. Individuals with β-TM usually present within the first two years of life with severe anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions. β-thalassemia intermedia is less severe than β-thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation therapy to remove the excess iron.
It is known that defective β-globin chain synthesis leads to the accumulation of free α-globin chains that form toxic aggregates 1,2. However, despite extensive knowledge on the molecular defects causing β-TM, little is known about the mechanisms responsible for ineffective erythropoiesis (IE) in β-TM patients. In such individuals, erythropoiesis does not result in the production of mature erythrocytes but instead is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage 3-5. This lack of understanding of the mechanism has prevented the development of effective strategies for treating the disease.
Humans are capable of producing three types of Hb chains: α, β and γ. The main oxygen transport protein in the human fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months of age is (α/γ)2 Hb. As the nomenclature indicates, this type of Hb tetramer contains two α globin subunits and two γ globin subunits. After about 6 months of age, humans shift from production of (α/γ)2 Hb toward production of (α/β)2 Hb, and in non-β-TM adult humans, (α/γ)2 Hb represents only about 1% or less of hemoglobin. However, the amount of (α/γ)2 Hb is increased in individuals with β-TM. Functionally, fetal hemoglobin differs from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother's bloodstream. Thus, the production of (α/γ)2 by β-TM cells could, in theory, be a boon for those suffering from thalassemias. However, since β-TM erythrocytes generally fail to mature, the presence of the alternate form of Hb is not especially useful to patients with this disease.